Diabetes is caused by multiple factors and is most simply characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting or post glucose-challenge state. Diabetes is a global epidemic affecting more than 240 million people worldwide. The incidence of this disease is growing fast. Each year 3.8 million people die from complications of diabetes, including heart disease, stroke and kidney failure. Metabolic abnormalities in carbohydrate, fat, and protein metabolism contribute to chronic hyperglycemia that leads to microvascular and macrovascular complications. There are two generally recognized forms of diabetes: Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), in which insulin is either absent or nearly absent because of autoimmune destruction or dysfunction of insulin-producing β-cells of the pancreas, and Type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), wherein patients produce some insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while simultaneously displaying hyperglycemia. Type 2 diabetes is the most prevalent abnormality of glucose homeostasis, accounting for approximately 90-95% of all cases of diabetes. Type 1 diabetes is typically treated with exogenous insulin administered via injection. However, Type 2 diabetes frequently develops insulin resistance, such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues such as muscle, liver and adipose tissues is diminished. Patients who are insulin resistant but not diabetic may have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated. In patients with Type 2 diabetes, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia.
At disease onset, hyperglycemia elicits elevated levels of circulating insulin in most individuals, but they have decreased peripheral glucose utilization and impaired suppression of endogenous glucose production as a result of insulin resistance. Decline of β-cell function tends to be progressive, and can ultimately result in an insulin-dependent state. Type 2 diabetes mellitus is associated with obesity, older age, physical inactivity, certain racial ethnicity populations, a family history of Type 2 diabetes, a history of gestational diabetes, or impaired glucose metabolism (impaired glucose tolerance (IGT), or pre-diabetes).
Diabetes can be treated with a variety of therapeutic agents, including insulin sensitizers, such as PPAR-γ agonists, such as glitazones and glitazars; biguanides; dipeptidyl peptidase-IV (DPP-IV) inhibitors; glucagon-like peptide-1 (GLP-1) agonists; insulin; insulin mimetics; sulfonylureas; meglitinides; and α-glucosidase inhibitors.
Increasing the plasma level of insulin by administration of sulfonylureas or meglitinides, which stimulate the pancreatic β-cells to secret more insulin, or by injection of insulin when sulfonylureas or meglitinides become ineffective, can result in insulin concentrations high enough to stimulate insulin-resistant tissues. However, dangerously low levels of plasma glucose can result, and increasing insulin resistance due to the even higher plasma insulin levels can occur. The biguanides have an unknown mechanism of action but decrease hepatic glucose output and increase insulin sensitivity resulting in some correction of hyperglycemia. Metformin monotherapy is often used for treating Type 2 diabetic patients who are also obese or dyslipidemic. Lack of appropriate response to metformin is often followed by treatment with sulfonylureas, thiazolidinediones, insulin, or α-glucosidase inhibitors. However, the two biguanides, phenformin and metformin, can also induce lactic acidosis and nausea/diarrhea, respectively. α-Glucosidase inhibitors, such as acarbose, work by delaying absorption of glucose in the intestine.
The PPAR-γ agonists, including glitazones, also known as thiazolidinediones (i.e. 5-benzylthiazolidine-2,4-diones) and non-thiazolidinediones, i.e. glitizars, represent another class of compounds with potential for improving many symptoms of Type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of Type 2 diabetes leading to partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. PPAR-γ agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones.
GLP-1 or glucagon-like peptide 1 is one of several incretin compounds that have biologic activity. After release into the blood by the intestine in response to food intake, GLP-1 slows food absorption. This delay in absorption allows the slow insulin response found in Type 2 diabetes to catch up. Improved insulin production also occurs when people take GLP-1 agonists. Both an increase in beta cell mass and improvement of first phase insulin release toward normal have been seen with this drug. Researchers hope that this action may delay progression of Type 2 diabetes or possibly assist in recovery of beta cell activity in early Type 1 diabetes. GLP-1 agonists have multiple sites of action. Giving natural GLP-1 was found to have little benefit because it is broken down by an enzyme called DPP-4 (dipeptidyl peptidose IV) within about 5 minutes. This lead to a search for modified GLP-1 molecules like Byetta, produced by Amylin and Lilly that are not broken down as quickly. Related to the GLP-1 agonists is a second new class of diabetes medications called DPP-4 inhibitors which work by delaying the breakdown of GLP-1, as well as other incretins. Because DPP-4 is involved in the breakdown of several peptides in the body, it will take time to be sure there are no unwanted side effects.
Abnormal glucose homeostasis is also associated both directly and indirectly with obesity, hypertension and alterations in lipid, lipoprotein and apolipoprotein metabolism. Obesity increases the likelihood of insulin resistance, and increases the likelihood that the resulting insulin resistance will increase with increasing body weight. Therefore, therapeutic control of glucose homeostasis, lipid metabolism, obesity and hypertension are critically important in the prevention of and clinical management and treatment of diabetes mellitus.
Despite the availability of a range of agents to treat type 2 diabetes, glucose control remains suboptimal, with less than 50% of patients achieving stated glycemic goals. In addition, current therapies have limited durability and/or are associated with significant side effects such as GI intolerance, hypoglycemia, weight gain, lactic acidosis and edema. Thus, significant unmet medical needs remain. In particular, safer, better tolerated medications which provide increases efficacy and long-term durability are desired.
The obvious need for new approaches to treat patients with uncontrolled T2DM has urged continued exploration of alternative targets in organs involved in maintenance of glucose homeostasis. In T2DM, renal glucose reuptake contributes to elevated plasma glucose levels and the concomitant microvascular complications. Inhibitors of the sodium-dependent glucose cotransporter 2 (SGLT2) prevent renal glucose reabsorption from the glomerular filtrate and provide an insulin-independent way of controlling hyperglycemia.
In healthy individuals, greater than 99% of the plasma glucose that is filtered in the kidney glomerulus is reabsorbed, with less than 1% of the total filtered glucose being excreted in urine. This reabsorption process is mediated by two sodium-dependent glucose cotransporters (SGLTs): SGLT1, a low-capacity, high-affinity transporter expressed in the gut, heart and kidney, and SGLT2, a high-capacity, low-affinity transporter that is expressed mainly in the kidney. It is estimated that 90% of renal glucose reabsorption by SGLT2 dwelling on the surface of the epithelial cells lining the Si segment of the proximal tubule. The remaining 10% is probably mediated by SGLT1 residing on the more distal S3 segment of the proximal tubule. Humans with SGLT1 gene mutations experience glucose-galactose malabsorption, with frequent diarrhea and dehydration when on a glucose diet, confirming that SGLT1 is not the major glucose transporter in the kidney. In contrast, persistent renal glucosuria is the sole reported phenotype of humans with SGLT2 gene mutations [Meng, W.; Washburn, W. N. et al. J. Med. Chem. 2008, 51, 1145-1149; Washburn, W. N. J. Med. Chem. 2009, 52, 1785-1794].
Selective inhibition of SGLT2 would be desirable, since potentially serious gastrointestinal side effects associated with SGLT1 inhibition would be minimized. Selective inhibition of SGLT2 has been suggested to help the normalization of plasma glucose levels in patients with diabetes by preventing the renal glucose reabsorption process and promoting glucose excretion in urine [Oku, A. et al. Diabetes 1999, 48, 1794-1800]. This mode is most likely to be involved in a low risk of hypoglycemia, since there is no interference with the normal counter-regulatory mechanisms for glucose.
The natural product phlorizin is a potent glucosuric agent that was subsequently shown to be a nonselective SGLT inhibitor. However, phlorizin is not a suitable drug candidate since it inhibits SGLT1 and also it has metabolic instability due to its susceptibility to β-glucosidase-mediated cleavage. Researchers at the Tanabe Seiyaku disclosed the identification of selective, potent SGLT2 inhibitors as potential treatments for type 2 diabetes. Subsequently, Kissei disclosed two other series of O-glucoside containing SGLT2 inhibitors. To achieve a significant reduction of hyperglycemia with a concurrent increase of glucosuria, the metabolic instability of the O-glucoside linkage demanded oral administration of their lead compound as the ethyl carbonate prodrug sergliflozin.
Meanwhile, Bristol-Myers Squibb reported discovery of dapagliflozin, as a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes [Meng, W. et al. J. Med. Chem. 2008, 51, 1145-1149]. Dapagliflozin is a metabolically more robust C-aryl glucoside.
Considering the important impact of diabetes on public health and unmet medical needs of current therapy, it is no surprise that SGLT2 inhibitors are currently interesting topics of studies, which were published in the following review articles [Washburn, W. N. Expert Opin. Ther Patents 2009, 19(11), 1485-1499; Washburn, W. N. J. Med. Chem. 2009, 52, 1785-1794].